CILP-2 is a novel secreted protein and associated with insulin resistance
CILP-2 is a novel secreted protein and associated with insulin resistance
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CILP-2 是一种新型分泌蛋白，与胰岛素抵抗相关
DOI：
10.1093/jmcb/mjz016
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发表时间：
2019-12-01
影响因子：
5.5
通讯作者：
Yang, Gangyi
中科院分区：
文献类型：
--
作者：
Wu, Tong;Zhang, Qin;Yang, Gangyi
摘要软骨中间层蛋白2（CILP-2）是2型糖尿病（T2 DM）的易感基因。然而，CILP-2是否参与葡萄糖稳态和胰岛素抵抗（IR）的调节仍然是未知的。在目前的研究中，我们最初观察到，CILP-2作为一种分泌蛋白在条件培养基和过表达载体转染的细胞裂解物中检测到。然后我们发现循环CILP-2水平从正常到糖耐量受损逐渐增加，（糖尿病前期状态）再发展为糖尿病，与腰臀比、甘油三酯、空腹血糖、糖负荷后2 h血糖、HbA 1c、空腹胰岛素、糖负荷后2 h血浆胰岛素、和稳态模型评估胰岛素抵抗，但与HDL-C呈负相关。CILP-2在肥胖小鼠或T2 DM患者的肝脏和肌肉中表达增加，但在脂肪组织中表达减少。此外，我们证明CILP-2循环水平受到OGTT和艾塞那肽的影响。CILP-2过表达导致体内葡萄糖耐量受损和肝脏IR，并增加PEPCK表达，而抑制胰岛素受体和Akt激酶的磷酸化。基于这些发现，我们已经确定了CILP-2和PEPCK之间的直接相互作用，并表明CILP-2在调节肝脏葡萄糖产生中起着重要作用。
Abstract Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.